PROJECT SUMMARY Studies have shown that RNA translation plays important regulatory roles during oncogenic transformation, cancer progression and metastasis. Targeting RNA translation for cancer therapy has enormous potential. However, translational regulation during oncogenesis in the genome-wide basis remains largely unexplored, as most current cancer research still focuses on transcriptome. Here I propose to use an integrated experimental and computational genomics approach to systematically dissect the regulation of RNA translation and the functional roles of translation factors in human cancers. Aim 1 will examine genome-wide regulation of mRNA translation during oncogenic transformation mediated by various oncogenes and tumor suppressor genes. The result will reveal novel mechanisms and functional targets of translational regulation underlying oncogenic transformation and cancer heterogeneity. Aim 2 will study the functional roles of translation factors and their genome-wide targets during oncogenic transformation. The study will provide mechanistic insights for targeting translation factors for cancer therapy. Aim 3 will characterize the regulation of RNA translation and gene co- expression networks of translation factors in human cancer patient samples using proteomics and transcriptomics data from the Cancer Genome Atlas (TCGA) database. This analysis will show how the regulatory mechanisms discovered using the cancer cell line models in Aims 1 and 2 contribute to in vivo cancer progression and heterogeneity. Taken together, the proposed experiments will systematically dissect the functional roles and genome-wide targets of translational regulation and translation factors in human cancers. The results will provide a novel mechanistic basis for targeting RNA translation in cancer therapy. While I have received extensive interdisciplinary training in computational genomics, cancer biology and molecular biology, the K99/R00 award will help me develop experimental skills, including implementing next- generation sequencing technologies based and molecular biology techniques. The research will take advantage of the unique and complementary expertise of the principal investigator, my mentors (Dr. Kevin Struhl at Harvard Medical School and Dr. Aviv Regev at the Broad Institute of MIT and Harvard) and my collaborator (Dr. Jean Zhao at Dana Farber Cancer Institute). Harvard Medical School and the Broad Institute provide me with an exceptional training environment. The proposed research will facilitate my career development to be an independent scientific investigator working at the forefront of cancer systems biology and developing novel therapeutic strategies for human cancers.